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Cartilage proteoglycans in synovial fluid and serum in patients with inflammatory joint disease. relation to systemic treatment

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972
CARTILAGE PROTEOGLYCANS IN SYNOVIAL FLUID
AND SERUM IN PATIENTS WITH
INFLAMMATORY JOINT DISEASE
Relation to Systemic Treatment
TORE SAXNE, DlCK HEINEGARD. and FRANK A. WOLLHEIM
Proteoglycan concentrations in knee joint synovial fluid and in serum from patients with various
inflammatory arthritides were studied using an enzymelinked immunosorbent assay. Patients with reactive
arthritis, calcium pyrophosphate arthropathy, and juvenile rheumatoid arthritis (age 5 2 0 years) had the
highest synovial fluid concentrations. These values differed significantly (P < 0.001) from those in patients
with rheumatoid arthritis, psoriatic arthropathy, and
chronic HLA-B27-associated arthropathy Rheumatoid
arthritis patients receiving low-dose prednisolone treatment had higher synovial fluid (P = 0.006) and serum
(P<: 0.001) proteoglycan concentrations than did those
taking nonsteroidal antiinflammatory drugs or slowacting antirheumatic drugs. Serum proteoglycan concentrations were near the detection limits, and did not
correlate with levels found in paired samples of knee
joint synovial fluid. Patients with calcium pyrophosphate arthropathy had the highest mean serum level of
proteoglycan. This assay of proteoglycan antigens is a
.
From the Department of Rheumatology, University Hospital, and the Department of Physiological Chemistry, University of
Lund, Lund, Sweden.
Supported by grants from Folksams Yrkesskadors stiftelse,
the Swedish Medical Research Council (no. 05668), the Faculty of
Medicine, University of Lund, the Greta och Johan Kocks stiftelser,
the Alfred Osterlunds stiftelse, the Riksforbundet mot Reumatism,
the Stiftelsen BistHnd %tVanfora i Sklne, and the Lasarettets i Lund
fonder.
Tore Saxne, MD, PhD: Research Fellow, Department of
Rheumatology, University Hospital; Dick HeinegLd, MD, PhD:
Professor, Department of Physiological Chemistry, University of
Lund; Frank A. Wollheim, MD, PhD: Professor, Department of
Rheumatology, University Hospital.
Address reprint requests to Dr. Tore Saxne, Department of
Rheumatology, University Hospital, S-221 85 Lund, Sweden.
Submitted for publication November 20, 1986; accepted in
revised form March 9, 1987.
Arthritis and Rheumatism, Vol. 30, No. 9 (September 1987)
useful tool in the study of proteoglycan metabolism in
patients with joint disease. With its use, differences
between disease groups and effects of therapy can be
distinguished.
Aside from collagen, proteoglycan is the main
component of articular cartilage. This macromolecule
constitutes approximately 20% of the dry weight of
cartilage (1). It consists of a central protein core to
which negatively charged glycosaminoglycan side
chains, chondroitin sulfate and keratan sulfate, are
covalently attached. Most of the proteoglycans form
aggregates by binding to hyaluronic acid by way of a
globular domain in the N-terminal region of their core
protein. These aggregates may have molecular weights
that exceed 100 x lo6 (2). Cartilage proteoglycans are
degraded very early in the course of joint disease (3).
The fragments formed are liberated to the synovial
fluid and may subsequently either reach the circulation, probably by way of the lymphatic system, or be
eliminated in the lymphatic system itself (4).
In previous studies of proteoglycan metabolism
in arthritis, investigators quantified proteoglycans as
glycosaminoglycans that were released to blood (9,
urine (6,7), and synovial fluid (8,9). Interpretation of
these results has been hampered by difficulties in
determining the source of the molecules that contain
the glycosaminoglycans, since the character of these is
not tissue-specific. Recently, however, greater specificity has been obtained by analyzing serum levels of
keratan sulfate, which is derived mainly from different
types of cartilage (10).
We have developed a specific enzyme-linked
immunosorbent assay (ELISA) for measuring proteoglycan antigens in synovial fluid (1 1). This assay has
973
CARTILAGE-DERIVED PROTEOGLYCANS IN SF
500
0
0
0
0
0
1 oc
0
0
0
0
0
0
8
q
0
8
0
v
m
0
9
0
8
0
i?
B
0
0
0
8
0
4-
0
9
d
4-
00
0
0
2-
8
W
1c
+
8
8
0
08
83
%
a
u
NSAlDs
(n = 143)
SAARDs
(n = 59)
0
i
0
8
8
8
0
3-
0
0
0
Glucocort.
X-ray
Glucocort.
(n = 31)
matched,
+ SAARDs
NSAlDs (n = 20) (n = 32)
Figure 1. Proteoglycan concentrations (logarithmic scale) in synovial fluids from patients with rheumatoid arthritis, according to
treatment group. Patients treated with glucocorticoids (Glucocort.),
with or without concomitant treatment with slow-acting antirheumatic drugs (SAARDs), had significantly higher (P= 0.006) levels of
proteoglycans than did those treated with nonsteroidal antiinflammatory drugs (NSAIDs) alone or those treated with SAARDs alone.
Glucocorticoid-treated patients also had significantly higher (P =
0.002) proteoglycan levels compared with patients who were taking
NSAIDs and who had equal cartilage destruction in the affected
knee joint, determined radiographically. Bars show medians.
now been modified to allow measurement of proteoglycan fragments in serum. In the present study, we
measured the concentrations of proteoglycan antigens
in the synovial fluid and serum of patients with inflammatory arthritides. We also analyzed the effects of
systemic therapy on proteoglycan concentrations in
the synovial fluid and serum of patients with rheumatoid arthritis (RA).
PATIENTS AND METHODS
Collection of synovial fluid and blood specimens.
Paired samples of knee joint synovial fluid and blood were
collected from patients attending the Department of
Rheumatology, University Hospital, Lund. All samples from
8
+
7
0
0
0
0
8
B
a
0
0
&
0
0
0
a
0
0
8
a
a
0
a
0
0
0
01
DP
Gold
Glucocort.
(n = 31) (n = 22) (n = 7 )
AZA
(n = 7)
Podo.
(n = 14)
Chloro.
(n = 39)
Figure 2. Proteoglycan concentrations (logarithmic scale) in
synovial fluids from patients with rheumatoid arthritis, according to
treatment with glucocorticoids (Glucocort.), with or without a
slow-acting antirheumatic drug (SAARD) (O),or treatment with an
SAARD only (0).Bars show medians. DP = D-penicillamine; Gold
= sodium aurothiomalate;AZA = azathioprine; Podo. = podophyllotoxin; Chloro. = chloroquine.
patients with definite or classic RA (12), calcium pyrophosphate arthropathy, reactive arthritis (13), psoriatic arthropathy, juvenile rheumatoid arthritis (JRA) (14), and
HLA-B27-associated arthropathy (ankylosing spondylitis
with peripheral joint involvement or asymmetric chronic
oligoarthritis) that had been collected during a 2.5-year
period were included in the study. For ethical reasons, no
blood samples were drawn from the young JRA patients. As
an alternative, sera that had been collected for other purposes from other JRA patients were used for comparison.
Complete aspirations of joint fluid were performed
under aseptic conditions, using a 1.2-mm bore needle, and
the total volumes were measured. No local anesthetic was
used. The effusions were collected into sterile tubes with
EDTA (5 mmolesAiter), centrifuged within 1 hour (at 1,800g
for 20 minutes, twice) to remove cells, and then stored at
-80°C. In some cases, synovial fluid was also collected into
tubes without additives. Analytic results of proteoglycan
concentration measurements were found to be independent
of the procedure used to collect the samples.
SAXNE ET AL
Blood samples were collected into sterile tubes without additives. The blood was allowed to clot for 2 hours at
room temperature. and then was centrifuged and stored at
-80°C. In initial experiments, the results obtained with
plasma samples did not differ from those obtained with
serum (data not shown).
The pharmacotherapy administered to the RA patients is shown in Figures l and 2. Thirty-one patients had
been treated with low-dose prednisolone (median 4.1
mglday, range 0.5-7.5) for a median of 4 years (range 0.5-20
years). Ninety-one patients had been treated with a slowacting antirheumatic drug (SAARD) for more than 3 months.
Of these patients, 32 had concomitant treatment with
glucocorticoids. The median treatment period for those who
took D-penicillamine, sodium aurothiomalate, azathioprine,
or podophyllotoxin was 7 months (range 3-32 months).
Patients taking chloroquine had been treated for a median of
3 years (range 0.25-12 years).
The drugs were given in commonly used dosages,
i.e., 1)-penicillamine 250-750 mg/day, sodium aurothiomalate 50 mg/week (intramuscular injection), azathioprine 2-2.5
mg/kg/day, podophyllotoxin 200-300 mg/day, and chloroquine 250 mglday. (Two patients who took chlorambucil, 6
mg/day, are included in Figure 1, but are not shown separately in Figure 2).
Ten RA patients had not received any oral medica-
tion during a 3-month period before joint aspiration. All
other RA patients were taking nonsteroidal antiinflammatory
drugs (NSAIDs). Except for 2 patients with calcium
pyrophosphate arthropathy, 8 patients with reactive arthritis, 3 patients with psoriatic arthropathy, and 6 patients with
JRA, all patients in the other disease groups were treated
with an NSAID. Six patients with JRA were treated with
prednisolone, 2 received gold injections, and 1 took
chloroquine. Only the group of patients with RA was large
enough to allow analysis of proteoglycan levels in relation to
therapy.
Radiographs of the knee joints were obtained. These
were read by a radiologist (Dr. H. Pettersson) who had no
knowledge of the patient’s clinical status. Radiographs were
graded 0-5, according to the method of Larsen et a1 (15). A
score of 5 denotes the most severe joint destruction.
C-reactive protein levels were measured, using
electroimmunoassay (16), at the Department of Clinical
Chemistry, Malmo General Hospital (Malmo, Sweden).
Analysis of proteoglycans. Proteoglycans were analyzed by ELISA, as described elsewhere (11). Briefly,
synovial fluids and sera were digested with bovine testicular
hyaluronidase (type I-S; Sigma, St. Louis, MO) before
analysis. Human articular cartilage proteoglycan monomer
that had been digested with chondroitinase ABC was used to
coat the polyvinyl microtiter plates. The antiserum used was
Table 1. Characteristics of patients in whom proteoglycan concentrations were assessed*
Female/
male
Diagnosis
Age
Rheumatoid
arthritis
( n = 265)
Calcium pyrophosphate
arthropathy
( n = 11)
Reactive
arthritis
( n = 31)
Psoriatic
arthropathy
( n = 24)
Juvenile
rheumatoid
arthritis,
age 5-20
(n = 23)
Juvenile
rheumatoid
arthritis,
age >20
(n = 21)
HLA-B27associated
arthropathy
(n = 13)
62
(20-84)
l82/83
62
(57-65)
0/11
39
(23-55)
7124
40
(28-66)
Disease
duration
(years)
SF
proteoglycan
content
(kg/ml)
Synovitis
Joint WBC
duration
ESR
count
(years) (mm/hour) ( X IO-’/Iiter)
I
10
(0.1-60)
(0.1-9)
55
(2-164)
8.9
(0.1-80.0)
17.4
(0.7-427.5)
1
(1-7)
0.6
(0.1-4)
34
(5-68)
12.4
(0.3-25 .0)
170.5
(49.5-509.4)
0.1
(0.008-31)
0.5
(0.1-2)
27
(3-75)
1.9
(0.1-12.0)
7/17
7
(0.8-57)
1 .5
(0.2-9)
27
(6-76)
4.2
(0.1-21 .0)
16.4
(0.7-155.7)
14
(3-20)
9/14
7.5
(0.5-1 1)
1
(0.1-9)
21
(2-125)
0.7
(0.1-22.6)
102.6
(1.8-477.0)
38
(2 1-46)
11/10
18
(7-37)
1
(0.1-9)
36
(1-120)
8.9
(1.3-55.0)
13.1
(2.3-47.7)
39
(34-7 1)
3/10
5
1
(0.3-4)
45
(3-65)
8.8
(0.1-20.3)
10.2
(1.9-66.2)
(0.5-43)
* Except for number of femalesinumber of males, values are medians (ranges). ESR
sedimentation rate (Westergren); WBC = white blood cell; SF = synovial fluid.
153.9
(49.1-1,251.0)
=
erythrocyte
CARTILAGE-DERIVED PROTEOGLYCANS IN SF
at a dilution of 1:3,000, was added to the plates and
incubated for 5 minutes at room temperature. After rinsing,
alkaline phosphatase-conjugated swine anti-rabbit IgG
(Orion Diagnostica, Helsinki, Finland), at a dilution of
1 :200, was added, and incubation was continued for 1 hour.
Chondroitinase-digested proteoglycan standards, diluted 1 : 1
in normal human serum, were analyzed for any serum
factors that might interfere with the results.
Statistical analysis. The Mann-Whitney test for
unpaired variables (2-tailed) was used to compare, differences between groups. Correlations were calculated using
Spearman's correlation coefficient and linear regression. P
values 10.05 were considered significant.
0
l0O0i
0
0
0
8
-8-
0
0
0
0
0
0
8
I
3-
0
0
8
I
I
i
0
0
1
0
0
0
0
0
0
0
RESULTS
0
Proteoglycan content in synovial fluid. There
was a wide distribution of synovial fluid proteoglycan
concentrations among patients in all of the groups
0
0
0
0
8
Q
8
I
0
0
0
0
1.c
0
0
-
0
0
0
!
8
0
0
-e
8
8
0
0
40
0.E
0
0
0
0
0'
RA
CPPD React.
(n = 265) (n = 11) arth.
975
B
t
0
0
Psor.
JRA,
JRA
HLA-627arth. age 5 20 age z 20 assoc. arth.
(n = 31) (n = 24) (n = 23) (n = 21) (n = 13)
Figure 3. Proteoglycan concentrations (logarithmic scale) in
synovial fluids from patients with inflammatory arthritides. Bars
show medians. RA = rheumatoid arthritis; CPPD = calcium
pyrophosphate arthropathy; React. arth. = reactive arthritis; Psor.
arth. = psoriatic arthropathy; JRA = juvenile rheumatoid arthritis;
HLA-B27-assoc. arth. = HLA-B27-associated arthropathy.
goat anti-human native articular cartilage proteoglycan
monomer. No ELISA-reactive material was detected iA
extracts of synovial tissue or bone, nor was any reaction
detectable using immunofluorescence techniques (Heinegbrd
D: unpublished observations).
A human articular cartilage proteoglycan monomer
standard was included in each microtiter plate. This standard
had been predigested with bovine testicular hyaluronidase
(0.5 mg of hyaluronidase per mg of proteoglycan) for 4 hours
at 37°C. Thus, the results are expressed as intact
proteoglycan monomer equivalents.
Serum samples were analyzed at a final dilution of
1:4, and synovial fluid samples were analyzed at a final
dilution of 1 : 18. The first ahtibody was used at similar
dilutions in analyses of synovial fluid and serum ( 1 : 1,000).
To further increase the sensitivity of the assay, an additional
antibody step was performed. Rabbit anti-goat IgG (Sigma),
0.E
In
0
d
a
0.L
0.2
Pro t e o g Iy c an
(p g /m I1
Figure 4. Standard curves for the enzyme-linked immunosorbent
assays used. A, Unmodified assay used to analyze synovial flbid. B,
Modified assay used to analyze serum (see Patients and Methods for
details), showing that the serum assay is more sensitive. C, Assay in
which the standard samples were diluted in normal human serum,
showing that serum factors do not influence the assay.
SAXNE ET AL
(Table 1 and Figure 3). The highest values were found
in synovial fluid samples from patients with calcium
pyrophosphate arthropathy , reactive arthritis, and
JRA (those 520 years old). Patients with RA, psoriatic
arthropathy , JRA (age >20), and HLA-B27-associated arthropathy had significantly lower proteoglycan
concentrations (P < 0.001). There was no significant
difference between these levels in patients with
polyarticular or oligoarticular JRA. Estimation of the
total amount of proteoglycan (by multiplying the concentration by the volume of aspirated fluid) yielded the
same findings (data not shown).
A more detailed study of the patients’ histories
showed that variations in age, duration of disease, and
duration of local synovitis among the disease groups
(Table 1) could not account for the observed differences in proteoglycan concentrations. Furthermore,
the synovial fluid proteoglycan concentration was not
significantly correlated with any of these 3 variables
within any of the disease groups. Moreover, there was
no significant correlation between the synovial fluid
proteoglycan concentration and the Westergren erythrocyte sedimentation rate, the blood levels of Creactive protein and hemoglobin, or the joint fluid
leukocyte count. Nor was there a correlation with the
Ritchie index of joint tenderness (17).
Proteoglycan content in serum. Figure 4 shows
that rhe assay modifications moderately inlproved the
sensitivity, and that serum factors do not influence the
assay results. Serum concentrations of proteoglycans
were much lower (range for all sera tested was 0.322.42 pg/ml) than the synovial fluid concentrations
(Figure 5). Patients with calcium pyrophosphate arthropathy had significantly higher serum proteoglycan
concentrations than did patients with RA ( P < 0.005),
patients with reactive arthritis ( P < O.OOl), and patients with psoriatic arthropathy (P < 0.001), as well
as the normal blood donors (P < 0.002). There was no
significant difference in serum proteoglycan levels in
JRA patients versus patients with calcium pyrophosphate arthropathy. No other differences in serum
concentrations were statistically significant. Serum
proteoglycan concentrations showed no correlation
with the synovial fluid proteoglycan concentrations.
Proteoglycan content in relation to therapy, in
synovial fluid and serum from RA patients. The patients
with RA were subgrouped according to current treatment. Almost all patients had received treatment with
an NSAID, and most of the patients in all of the
subgroups were currently taking such a drug. Ten
patients who had received no medication had synovial
0
0
0
. o
8
8
0
0
4-
i
0
0
da
0
0
0
8
J
1
-Q-
1
0
80
0
8
8
RA
CPPD
= 9)
(n = 30) (n
React.
arth.
(n = 22)
0
€8
Psor.
JRA,
Normal
arth.
age c 20 donors
(n = 17) (n = 13) (n = 30)
Figure 5. Proteoglycan concentrations in serum samples from patients with inflammatory arthritides and from normal blood donors.
Bars show medians. See Figure 3 for definitions.
fluid proteoglycan concentrations similar to those in
patients who were being treated with NSAIDs. Sixtythree patients had been treated with glucocorticoids.
With or without concomitant treatment with SAARDs,
these patients had significantly higher ( P = 0.006)
synovial fluid proteoglycan concentrations than did
those who were receiving an NSAID or an SAARD
alone. The difference in synovial fluid proteoglycan
concentrations was even more pronounced (P= 0.002)
in comparisons of patients treated with glucocorticoids
alone versus radiographically matched patients who
had not had such treatment (Figure 1). The median
value in the glucocorticoid-treated patients was approximately 30 pg/ml, compared with a level of approximately 15 pglml in the other patients.
The entire group of patients who were taking
glucocorticoids had more advanced destruction of the
knee joints seen on radiographs (Larsen index), than
did the remainder of the RA patients (P< 0.05). The
glucocorticoid-treated patients were somewhat older
(median age 63, range 35-82) than the patients treated
977
CARTILAGE-DERIVED PROTEOGLYCANS IN SF
with SAARDs (median age 57, range 34-82) (P <
0.05), but they were not significantly older than the
patients receiving NSAIDs (median age 63, range
20-84). No other apparent differences in clinical or
biochemical variables were found among the different
groups.
The higher concentration of synovial fluid
proteoglycans in glucocorticoid-treated patients is also
shown in Figure 2, in which the patients are grouped
according to treatment with glucocorticoids and various SAARDs. The majority of the patients treated
with both glucocorticoids and SAARDs had higher
proteoglycan concentrations than did those treated
with SAARDs only. No SAARD showed an effect on
the synovial fluid proteoglycan concentration that was
different from the effect of an NSAID alone.
Higher serum proteoglycan concentrations (P
< 0.001) were observed among the glucocorticoidtreated patients compared with a group of RA patients
who were not treated with glucocorticoids, but who
had the same degree of cartilage destruction, as seen
on radiographs of the aspirated knee joint (Figure 6).
DISCUSSION
In previous work, we established that the
synovial fluid proteoglycan concentration is inversely
related to cartilage destruction as assessed radiologically (18). Assay of proteoglycans, then, would not be
of great interest in a patient with end-stage erosive
disease, but in earlier stages of disease, such measures
would be of benefit. The findings in this study amplify
and confirm this. Since newly synthesized proteoglycans have been shown to be retained in the cartilage
(19), and the proteoglycans detected in the synovial
fluid largely represent partially fragmented macromolecules (20), it is likely that the synovial fluid proteoglycan levels reflect the degree of degradation.
Conversely, the synovial fluid proteoglycan
content is higher in patients with calcium pyrophosphate arthropathy and in those with reactive arthritis,
despite the low frequency of long-term cartilage destruction in patients with these diseases. Apparently,
in these conditions, the ability to replace proteoglycans that are lost from the cartilage matrix is sufficient
to avoid permanent destruction.
In monitoring patients with reactive arthritis
who were not receiving therapeutic intervention, we
found the highest synovial fluid proteoglycan levels
during the early stages of the disease, whereas a
steady decrease in these levels was seen as the clinical
0
0
0
2.0
8
0
0
1 .c
0
0
0
80
0
0
Glucocort.
(n = 26)
80
X-ray matched,
no Glucocort.
(n = 22)
Figure 6. Proteoglycan concentrations in serum samples from patients with rheumatoid arthritis, according to treatment (with glucocorticoids [Glucocort.I or without glucocorticoids). Glucocorticoidtreated patients had significantly higher (P < 0.001) proteoglycan
levels compared with patients who were not taking glucocorticoids
and who had equal cartilage destruction in the affected knee joint,
determined radiographically. Bars show medians.
manifestations of the arthritis subsided (1 1). This
might imply that the high concentrations of synovial
fluid proteoglycans are a reflection of the acute nature
978
of the arthritis rather than a reflection of the specific
disease. However, a comparison of patients with reactive arthritis and those with rheumatoid arthritis,
stratified according to the degree of cartilage destruction and duration of synovitis, showed significantly
higher ( P < 0.001) synovial fluid proteoglycan concentrations among the patients with reactive arthritis (18).
This finding suggests that proteoglycan metabolism
differs in these disease groups.
The high concentrations of synovial fluid
proteoglycans in the younger patients with JRA (those
5 2 0 years) suggested an age-related change in proteoglycan metabolism. However, in studies of synovial
fluid from the hip joints of children with transient
synovitis but no other signs of arthritis, it was found
that proteoglycan concentrations were similar to those
in the hip joints of adults (21). Furthermore, we found
no relationship between the synovial fluid proteoglycan concentration and the patient’s age. The patients with HLA-B27-associated arthropathy and
psoriatic arthropathy, who in this study, showed no
signs of radiologic damage and were of the same age as
the patients with reactive arthritis, had significantly
lower ( P < 0.001) synovial fluid proteoglycan concentrations than did those with reactive arthritis. Thus,
the differences in age distribution between the disease
groups cannot explain the differences in proteoglycan
concentrations.
The lack of correlations between synovial fluid
proteoglycan concentrations and markers of inflammation in blood and synovial fluid indicates that there is
no close connection between the generalized inflammatory response and the proteoglycan metabolism in
an individual cartilage. Thus, synovial fluid proteoglycans are markers for the process that damages the
cartilage. This process may progress independently of
more generalized inflammation, as measured by conventional biochemical markers.
In previous attempts to measure levels of
synovial fluid proteoglycans, various chemical methods have been used to determine the glycosaminoglycan content. Those methods lack the specificity of
our assay, and meaningful comparisons of results are
therefore precluded. However, Gysen and coworkers
(22), using a radioimmunoassay to study synovial fluid
proteoglycan concentrations in RA patients, found
that the mean concentration was 12.6 pg/ml (n = 15).
That result is consistent with our findings.
Serum concentrations of proteoglycan are low
compared with synovial fluid concentrations. This
may be because proteoglycan molecules are rapidly
SAXNE ET AL
taken up and degraded by liver endothelial cells in a
manner similar to that of hyaluronate (23). It is apparent, however, that there is no information on either the
influx of proteoglycan fragments to the circdation or
their elimination. Therefore, the results should be
interpretated with caution.
An unexpected and intriguing observation in
this study was the higher synovial fluid and serum
proteoglycan concentrations in RA patients receiving
low-dose oral glucocorticoid treatment. These findings
should be investigated in a prospective study. The
available data do not allow conclusive interpretation,
but could indicate increased proteoglycan degradation
and permanent cartilage destruction. Another possible
explanation, although less likely, is that glucocorticoids eliminate a factor that inhibits chondrocyte
function, allowing more synthesis of proteoglycan.
For reasons already discussed, this alternative interpretation is probably not the correct one. Hunneyball
(24), in fact, in studies of rabbits with experimental
arthritis, found decreased glycosaminoglycan content
in the menisci during systemic treatment with
prednisolone. He interpreted this finding to be a result
of inhibition of protein synthesis (24). It has been
shown that intraarticular administration of crystalline
glucocorticoids to patients with arthritis lowers the
synovial fluid proteoglycan content (1 1). This effect
could presumably be the result of reduced interleukin1 release from the synovial membrane and a lower
catabolic effect. Thus, it appears that glucocorticoids
act in several ways in the inflamed joint, and that this
action is, perhaps, dependent on dosage and route of
administration.
The SAARDs studied here do not differ in their
effects on proteoglycan metabolism, nor do they differ
in this respect compared with NSAIDs. In contrast,
Chuck and coworkers (7) have shown that total urinary excretion of glycosaminoglycans decreased after
disease response to treatment with a second-line drug
(chloroquine, gold, penicillamine), but not during
treatment with NSAIDs. Pritchard (25) has found
reduced levels of uronic acid in synovial fluids of RA
patients treated with gold or penicillamine, compared
with patients taking only an NSAID.
Synovial fluid and serum proteoglycan analyses
represent new ways to study diseases that involve
cartilage. These methods combined with measurements of other components released from cartilage,
such as keratan sulfate (lo), will, presumably, enable
us to obtain better insight into the nature of cartilage
metabolism in joint disease, and to understand the
CARTILAGE-DERIVED PROTEOGLYCANS IN SF
different mechanism involved in healing a n d advancing
tissue damage. The assays will be useful in t h e search
for improved drugs as well as in the exploration of the
relation between inflammation a n d destruction.
ACKNOWLEDGMENTS
We are grateful to Dr. Holger Pettersson for examining the radiographs, to Siv Valterson for skillful technical
assistance, and to all staff members of the Department of
Rheumatology, University Hospital who helped to collect
samples.
REFERENCES
1. Saklatvala J: The non-collagenous matrix of cartilage:
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